The present invention relates to hydroxymethyl derivatives of 5-benzylacyclouridine and 5-benzoyloxybenzylacyclouridine and to their use in the potentiation of pyrimidine nucleosides such as 5-fluoro-2'-deoxyuridine (FdUrd) in cancer chemotherapy by way of uridine phosphorylase inhibition.
The efficacy of the chemotherapeutic agent FdUrd is limited by its cleavage to the less effective base 5-fluorouracil (Fura). Two enzymes are responsible for the cleavage, thymidine phosphorylase and uridine phosphorylase.
There has been a great deal of interest in developing inhibitors of FdUrd degradation. In contrast to normal tissues, many neoplasms are deficient or have a low activity level of thymidine phosphorylase as compared to uridine phosphorylase. It has been proposed that by coadministering a uridine phosphorylase inhibitor with FdUrd, the activity of FdUrd can be selectively directed against the tumor cells and not against the host tissues. With coadministration of a uridine phosphorylase inhibitor, the host tissues should retain their capacity to cleave FdUrd to FUra by thymidine phosphorylase, but in tumors in which the activity of thymidine phosphorylase is low or absent, with inhibition of uridine phosphorylase, FdUrd retains its efficacy.
A series of acyclouridines have been developed as inhibitors of uridine phosphorylase. See Niedzwicki, et al., "5-Benzylacyclouridine and 5-Benzyloxybenzylacyclouridine, Potent Inhibitors of Uridine Phosphorylase" Biochem. Pharmacol., 31: 1857-1861, 1982 and Niedwicki, et al., "Pyrimidine Acyclonucleoside, Inhibitors of Uridine Phosphorylase," Biochem. Pharmacol., 30:2097-2101, 1981. Among the acyclouridines which have been developed, 5-benzylacyclouridine (BAU) and 5-benzyloxybenzylacyclouridine (BBAU) have been particularly effective. It has been shown that these compounds inhibit the cleavage of FdUrd in certain tumor extracts and enhance the antineoplastic activity of FdUrd on human pancreatic carcinoma (DAN) and human lung carcinoma (LX-1) cell lines in vitro and in vivo. See Chu et al., "Potentiation of 5-Fluoro-2'deoxyuridine Antineoplastic Activity by the Uridine Phosphorylase Inhibitors Benzylacyclouridine and Benzyloxybenzylacyclouridine," Cancer Res. 44, 1852-56, May 1984. BAU and BBAU, however, are not very water soluble.